Asthma drug offers new mechanism for diabetes and fatty liver treatment

Paul Basilio, MDLinx | July 14, 2017

A drug used to treat asthma in Japan my improve fatty liver disease and insulin sensitivity in patients with higher levels of inflammation in their fat tissue, according to researchers at Michigan Medicine and the University of California, San Diego. The study is published in Cell Metabolism.

Advertisement

Elif Oral, MD, an endocrinologist at Michigan Medicine, led a clinical trial of an asthma drug that shows promise as an obesity and diabetes medication.

The drug, amlexanox, appeared to free the metabolic system to burn more energy in this particular subset of patients, and revealed an inflammatory link between obesity and type 2 diabetes.

“We are beginning to understand the role this form of internal inflammation plays in the development of chronic diseases like diabetes,” said lead study author Elif Oral, MD, Director of the MEND Obesity and Metabolic Disorder Program at Michigan Medicine. “Ultimately, we may be able to personalize therapy based on the degree of inflammation present at baseline – which is a new concept.”

Dr. Oral is an endocrinologist and translational scientist at the University of Michigan’s academic medical center, where the clinical trial was conducted and analyzed. Tissue analysis was performed by study author Alan R. Saltiel, PhD, from UC San Diego, in addition to scientists at the Salk Institute for Biological Sciences in La Jolla, CA.

In the study, researchers identified a molecular signature in obese patients with type 2 diabetes who responded to amlexanox.

“When we looked at the drug-treated group, we saw a bimodal distribution—there were some responders and some non-responders,” said Dr. Saltiel, Director of the Institute for Diabetes and Metabolic Health at UC San Diego. “We didn’t understand why, so we did a molecular analysis from biopsies of fat cells that we took from patients at the beginning and end of the study. In the responder group, the level of inflammation in fat was higher than in the non-responder group at the beginning of the study, indicating that there is something about inflammation that predisposes a person to respond. And, what was really amazing was that there were more than 1,100 gene changes that occurred exclusively in the responders.”

The glucose-lowering effects of amlexanox were first discovered in a mouse study at the University of Michigan by Dr. Saltiel, who served there as Director of the Life Sciences Institute.

Looking forward

Amlexanox is an inhibitor of the enzymes IKKε and TBK1. In previous studies, Dr. Saltiel and U-M researchers discovered that these enzymes are induced in obese mice, and can cause a decrease in energy expenditure.

Their search for inhibitors of these enzymes led them to amlexanox. The obese mice who received the drug lost weight, while their insulin sensitivity increased, which led to improvement in diabetes and fatty liver disease.

A human trial showed that the genetic changes present in the mouse model were also present in the human responder group. In humans, blood sugar decreased as the genes involved in the expenditure of energy changed.

The proof of concept trial began with an unblinded safety trial involving six patients. It was followed by a controlled trial of 42 patients with obesity and type 2 diabetes.

In the controlled study, half of the patients were randomized to a placebo group while the other half received amlexanox for three months. Blood sugar, insulin sensitivity, weight, and liver fat were measured. A biopsy specimen of fat cells from each patient’s midsection was examined before and after the trial to measure changes in gene expression.

“The most exciting part of this is that we have a new drug that has never been studied before,” said Dr. Saltiel. “It’s a new mechanism for a diabetes and fatty liver drug. It’s promising, but there are a lot of questions that need to be answered still.”

Additional investigation will determine which genetic changes are the most important to target, the appropriate dosage, how to increase the percentage of responders, and how long the beneficial effects can be sustained.

In the study, approximately one-third of the participants were responders. An improvement was also noted among responders with nonalcoholic fatty liver disease.

The team is now planning follow-up trials to determine whether it is possible to stratify patients who are likely to respond based on the degree of underlying inflammation, and ether other drugs can be combined with amlexanox.

“We are grateful for patient participation and hope that our patients will respond with the same enthusiasm to our new trials,” said Dr. Oral. “Without patients volunteering, the sort of study can never happen.”

For more information about this study, click here

Advertisement